This invention relates to vitamin D compounds, and more particularly to N-cyclopropyl-(20R)-2-methylene-19,26,27-trinor-25-aza-vitamin D analogs and their pharmaceutical uses, and especially N-cyclopropyl-(20R)-2-methylene-19,26,27-trinor-25-aza-1α-hydroxyvitamin D3, its biological activities, and its pharmaceutical uses.
The most active metabolite of vitamin D3, namely, 1α,25-dihydroxyvitamin D3, is a potent calcium and phosphorous regulating hormone playing an important role in bone homeostasis in animals and humans. Also, in addition to this classical role, the natural hormone elicits immunomodulation as well as cell differentiation and proliferation activities in numerous malignant cells and keratinocytes [Feldman et al, Vitamin D, 2nd ed,; Elsevier Academic Press: New York, 2005]. 1α,25-Dihydroxyvitamin D3 expresses these functions by binding to the vitamin D receptor (VDR), a ligand-regulated transcription factor. Structural analogs of this metabolite have been prepared and tested such as 1α-hydroxyvitamin D3, 1α-hydroxyvitamin D2, and various other side-chain and A-ring modified vitamins. Some potent synthetic analogs have been used clinically to treat bone disorders such as osteoporosis and the skin disorder—psoriasis. Some of these compounds exhibit separation of activities in cell differentiation and calcium regulation. The difference in activity may be advantageous in treating a variety of diseases such as renal osteodystrophy, vitamin D-resistant rickets, osteoporosis, and malignancies.
In U.S. Pat. Nos. 4,800,198, 5,089,641 and 5,366,731, a class of secosterol compounds has also been prepared which exhibit high growth inhibitory activity towards malignant cells, such as leukemia cells, but have significantly less of the undesired side-effects (potent calcemic action) of some of the known vitamin D compounds mentioned above. This selectivity and specificity of action makes the secosterols potentially useful as agents for the treatment of malignancies such as leukemia. These secosterol compounds have also been proposed for use in dermatological compositions to treat skin disorders such as dermatitis, eczema and psoriasis, as well as in cosmetic compositions to treat less sever skin conditions such as wrinkles, lack of dermal hydration, i.e. dry skin, lack of adequate skin firmness, i.e. skin slackness, and insufficient sebum secretion.
Calcipotriene is another synthetic vitamin D3 derivative that is marketed for topical dermatological use against psoriasis. Calcipotriene has a 24-cyclopropyl substituent, and is disclosed in U.S. Pat. No. 4,866,048.
Another class of vitamin D analogs, i.e. the so called 19-nor-vitamin D compounds, is characterized by the replacement of the A-ring exocyclic methylene group (carbon 19), typical of the vitamin D system, by two hydrogen atoms. Biological testing of 19-nor-analogs such as 1α,25-dihydroxy-19-nor-vitamin D3 revealed a selective activity profile with high potency in inducing cellular differentiation, and reduced calcium mobilizing activity. Thus, these compounds may be potentially useful as therapeutic agents for the treatment of malignancies, or the treatment of various skin disorders. Two different methods of synthesis of such 19-nor-vitamin D analogs have been described (Perlman. et al., Tetrahedron Lett. 31, 1823 (1990); Perlman et al., Tetrahedron Lett. 32, 7663 (1991), and DeLuca et al., U.S. Pat. No. 5,086,191).
In U.S. Pat. No. 4,666,634, 2β-hydroxy and alkoxy (e.g., ED-71) analogs of 1α,25-dihydroxyvitamin D3 have been described and examined by Chugai group as potential drugs for osteoporosis and as antitumor agents. See also Okano et al., Biochem. Biophys. Res. Commun. 163, 1444 (1989). Other 2-substituted (with hydroxyalkyl, ED-120, and fluoroalkyl groups) A-ring analogs of 1α,25-dihydroxyvitamin D3 have also been prepared and tested (Miyamoto et al., Chem. Pharm. Bull. 41, 1111 (1993) Nishii et al., Osteoporosis Int. Suppl. 1, 190(1993); Posner et al., J. Org. Chem, 59, 7855 (1994), and J. Org. Chem, 60, 4617 (1995)).
2-substituted analogs of 1α,25-dihydroxy-19-nor-vitamin D3 have also been synthesized, i.e. compounds substituted at 2-position with hydroxy or alkoxy groups (DeLuca et al., U.S. Pat. No. 5,536,713), with 2-alkyl groups (DeLuca et al U.S. Pat. No. 5,945,410), and with 2-alkylidene groups (DeLuca et al U.S. Pat. No. 5,843,928), which exhibit interesting and selective activity profiles. All these studies indicate that binding sites in vitamin D receptors can accommodate different substituents at C-2 in the synthesized vitamin D analogs.
In a continuing effort to explore the 19-nor class of pharmacologically important vitamin D compounds, analogs which are characterized by the presence of a methylene substituent at carbon 2 (C-2), a hydroxyl group at carbon 1 (C-1), and a shortened side chain attached to carbon 20 (C-20) have also been synthesized and tested. 1α-hydroxy-2-methylene-19-nor-pregnacalciferol is described in U.S. Pat. No. 6,566,352 while 1α-hydroxy-2-methylene-19-nor-homopregnacalciferol is described in U.S. Pat. No. 6,579,861 and 1α-hydroxy-2-methylene-19-nor-bishomopregnacalciferol is described in U.S. Pat. No. 6,627,622. All three of these compounds have relatively high binding activity to vitamin D receptors and relatively high cell differentiation activity, but little if any calcemic activity as compared to 1α,25-dihydroxyvitamin D3. Their biological activities make these compounds excellent candidates for a variety of pharmaceutical uses, as set forth in the '352, '861 and '622 patents.